Mutations in presenilins (PS1 and PS2) are causal for early-onset familial Alzheimer's disease (FAD). These mutations are known to alter the gamma-secretase processing of the amyloid precursor protein (APR), resulting in an elevated ratio of Abeta42/Abeta40, peptides that constitute the principal components of the amyloid plaque pathology characteristic of Alzheimer's disease. However, this increased ratio of Abeta42/Abeta40 does not provide mechanistic insights as it can result from elevated production of Abeta42, a reduction of Abeta40 or both combined. In the original grant application, we hypothesized that the PS FAD mutations lead to partial loss of activity on APP cleavage at the predominant Abeta40 site. Reduced production of Abeta40 is the primary cause for the increase in the ratio of Abeta42/Abeta40. Using our novel mouse genetic approach, we provided strong experimental support for this "partial loss-of-function" hypothesis for the PS FAD mutations, not only in gamma-secretase processing of APP, but also in other PS-mediated physiological pathways. Building on the partial loss-of-function hypothesis and our established mouse genetic systems, in particular the PS conditional knockout, PS1 FAD knock-in and our novel PS1 "rescue" system, in this competitive renewal, we propose to decipher the gamma-secretase dependent and gamma-secretase independent activities of PS and determine the effects of PS FAD mutations on tau phosphorylation, and neuronal and synaptic function in vivo. Furthermore, we will test our new hypothesis that NFkappaB and GSK are critical downstream effectors of PS by pharmacological and genetic manipulations combined with biochemical, immunohistochemical, electrophysiological and neuroimaging analyses. Presenilin plays a pivotal role in AD pathogenesis. Mutations in PS have been shown to affect both Abeta production and tau hyperphosphorylation, which are the determinants of the amyloid plaque and neurofibrillary tangle pathologies respectively. Therefore, delineating these PS-mediated pathways and investigating the mechanisms of PS mutations as proposed are critically important for our understanding of AD pathogenesis and for developing effective therapeutics that target the specific activities of presenilin.